This application describes a set of proposed studies and structured career development plan carefully crafted to assist the Principal Investigator acquire the skills and experience necessary for becoming an independent clinical investigator in the areas of sickle cell anemia (SCA) and exercise physiology. Under the guidance of a group of accomplished mentors and scientific advisors, the Principal Investigator will gain additional formal training in patient-oriented research methodology, biostatistics, cardiopulmonary disease and applied exercise physiology. The practical and classroom training proposed will occur at the Northwestern University Feinberg School of Medicine and the University of Illinois at Chicago, both highly regarded institutions with extensive track records for the development of young physician-scientists. The Principal Investigator is currently an Assistant Professor of Pediatrics at Northwestern and an Attending Physician in the Division of Hematology, Oncology &Stem Cell Transplant at Children's Memorial Hospital. The overall objective of this study is to use cardiopulmonary exercise testing to delineate the pathophysiologic mechanisms that contribute to the impaired exercise response and reduced exercise capacity observed in children and young adults suffering from SCA. Although cardiopulmonary disease and the acute inflammatory response to exercise may contribute to exercise limitation in the general population, their role in reducing exercise capacity in children with SCA has not been systematically addressed. The Specific Aims of this proposal are to: 1) Evaluate peak oxygen consumption (VO2) and other aerobic parameters of the cardiopulmonary response to exercise obtained from gas exchange analysis in children and young adults with SCA undergoing cardiopulmonary exercise testing;2) Characterize the acute inflammatory response to exercise, as measured by an increase in soluble vascular cell adhesion molecule (sVCAM) activity, in subjects undergoing cardiopulmonary exercise testing;and 3) Assess the longitudinal change in exercise capacity, as measured by peak VO2 on cardiopulmonary exercise testing, over a 2-year period in children and young adults with SCA. The paucity of data regarding the risks and benefits of exercise in children with SCA has contributed to the inability to develop recommendations for physical activity in this population despite the general consensus that regular exercise is beneficial for children who are both healthy and have a chronic medical condition. If achieved, the Specific Aims outlined in this proposal will yield critical data that will allow the Principal Investigator to develop evidence-based, exercise prescription programs aimed at improving physical functioning, exercise capacity and overall quality of life in children with SCA. Along with the mentoring and additional training gained from his proposed career development plan, the Principal Investigator will also be in the unique position to build upon these experiences as the basis for achieving future research independence.